Diabetes mellitus, whether IDDM or NIDDM, can be considered the result of inadequate mass of functional pancreatic B-cells, in the former due to a selective autoimmune destruction of these cells and the latter to an inability to compensate for the extra demand of obesity or insulin resistance. Once safe immunosuppression is available, both forms of diabetes could be treated if we could stimulate the growth and differentiation of B-cells either in vivo or as expansion of tissue available for transplantation. However, after twenty years of work with cultured neonatal or adult islets, only modest growth stimulation of pancreatic B-cells has been achieved and the regulation of B-cell growth is still poorly understood. However, greater stimulation of B-cell growth has been found in vivo models. After partial pancreatectomy, marked regeneration of islet tissue occurs; the remnant of 10% has 45% of the islet tissue of the sham animals after 6-8 weeks. This regeneration occurs by two pathways: 1) an enhanced rate of replication of preexisting pancreatic B-cells and 2) formation of new islets by differentiation of newly formed proliferating ductules. Coupling this model with the powerful new tools of cell and molecular biology offers a unique opportunity to study both the proliferation and differentiation of the pancreatic B-cell. There are three areas of this project: 1) the definition of the focal regions of newly formed tissue, 2) the screening of various growth factors for possible roles in both pathways of regeneration and 3) the in vitro testing of these candidate factors on cultured adult islet cells and adult duct epithelium. The definition of the focal regions of regeneration will make use of BUdR labelling of newly formed cells and of immunostaining at both the light and ultrastructural levels. The roles of growth factors will be initially studied by analyzing the expression of the mRNA of the factors and their receptors by S1 nuclease protection assay, dot blots and in situ hybridization. This project should contribute to the understanding of the presumably complex orchestration of factors regulating the growth and differentiation of the pancreatic B-cell.